While it has been appreciated for many years that radiation causes cell death, it has only recently become accepted that radiation has potential to enhance proliferation in the surviving fraction of cells. We have discovered that exposure of carcinoma cells radiation causes an initial activation of growth factor receptors in the plasma membrane, followed by secondary receptor activation that is dependent upon autocrine growth factors. In epithelial cells exposed to growth factors, coordinated signaling through H- and K-RAS isoforms into signaling pathways, via transcription factors, is thought to promote progression through G1 phase of the cell cycle. Significantly, the roles of the different isoforms of RAS and the signal transduction pathways utilized by radiation to promote or hinder G1 cell cycle progression and radiosensitivity of RAS-transformed tumor cells are not fully understood. In AIM 1, studies will determine using isogenic colon tumor cell lines in vitro whether basal and radiation-induced signaling is altered by expression of either mutant H- or mutant K-RAS. In AIM 2, studies will determine whether inhibition of a signaling pathway causes a RAS-dependent and ERBB-dependent shunting of radiation-induced signaling into the other parallel pathways. Studies in AIM 3 will determine whether low dose radiation promotes G1 progression in serum-starved tumor cells that lack P53 or P21 expression. We will confirm or refute the hypothesis that radiation-induced signaling in RAS-transformed tumor cells promotes G1 progression into S phase, that is dependent upon the actions of signaling pathways and the transcription factor C/EBPbeta. In addition, it is known that inhibition of RAS and the MAPK and AKT pathways can radiosensitize cells, however, the relative contributions of mutant H-RAS versus mutant K-RAS within the same cell type to radiosensitivity have not been delineated. Collectively, the studies in this proposal will mechanistically define the signaling pathways utilized by different RAS isoforms in the proliferative and survival responses of irradiated tumor cells.